U.S. patent application number 14/385069 was filed with the patent office on 2015-03-26 for polymorphic form of a long-acting beta-2 adrenoceptor agonist.
This patent application is currently assigned to LABORATORIOS LESVI S.L.. The applicant listed for this patent is Laboratorios Lesvi S.L.. Invention is credited to Jordi Benet-Buchholz, Jordi Ceron Bertran, Pere Dalmases Barjoan, Gl ria Freixas Pascual, Isabel Navarro Munoz.
Application Number | 20150087715 14/385069 |
Document ID | / |
Family ID | 47997575 |
Filed Date | 2015-03-26 |
United States Patent
Application |
20150087715 |
Kind Code |
A1 |
Benet-Buchholz; Jordi ; et
al. |
March 26, 2015 |
POLYMORPHIC FORM OF A LONG-ACTING BETA-2 ADRENOCEPTOR AGONIST
Abstract
New polymorphic form of a long-acting beta-2 adrenoceptor
agonist A new polymorphic form of arformoterol tartrate, designated
as form D, is provided and which is characterised by at least one
of the following: (i) a powder X-ray diffraction pattern having
peaks at approximately 6.8, 13.3, 13.6, 3.8, 14.1, 18.2, 18.7,
20.0.+-.0.2 degrees two theta; or (ii) a DSC thermogram showing an
endothermic peak with an onset at approximately 19-120.degree. C.,
and a maximum at approximately 129-131.degree. C., followed by an
exothermic peak with a maximum at approximately 137-138.degree. C.;
wherein the DSC thermogram of form D has a further endothermic peak
with an onset at approximately 168-170.degree. C.1 Processes for
preparing the new polymorphic form, uses thereof and intermediates
for the preparation thereof, are also provided.
Inventors: |
Benet-Buchholz; Jordi;
(Tarragona, ES) ; Ceron Bertran; Jordi;
(Tarragona, ES) ; Freixas Pascual; Gl ria;
(Tarragona, ES) ; Dalmases Barjoan; Pere;
(Barcelona, ES) ; Navarro Munoz; Isabel;
(Barcelona, ES) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Laboratorios Lesvi S.L. |
Barcelona |
|
ES |
|
|
Assignee: |
LABORATORIOS LESVI S.L.
Barcelona
ES
|
Family ID: |
47997575 |
Appl. No.: |
14/385069 |
Filed: |
March 12, 2013 |
PCT Filed: |
March 12, 2013 |
PCT NO: |
PCT/GB2013/050605 |
371 Date: |
September 12, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61609505 |
Mar 12, 2012 |
|
|
|
Current U.S.
Class: |
514/629 ;
562/585 |
Current CPC
Class: |
C07C 233/43 20130101;
A61P 11/08 20180101; C07C 231/16 20130101; C07C 231/24 20130101;
C07B 2200/13 20130101 |
Class at
Publication: |
514/629 ;
562/585 |
International
Class: |
C07C 233/43 20060101
C07C233/43; C07C 231/16 20060101 C07C231/16 |
Claims
1-15. (canceled)
16. A polymorphic form of arformoterol tartrate, designated as form
D, which is characterized by at least one of the following: (i) a
powder X-ray diffraction pattern having peaks at 6.8, 13.3, 13.6,
13.8, 14.1, 18.2, 18.7, 20.0.+-.0.2 degrees two theta; or (ii) a
DSC thermogram showing an endothermic peak with an onset at
approximately 119-120.degree. C., and a maximum at approximately
129-131.degree. C., followed by an exothermic peak with a maximum
at approximately 137-138.degree. C.; wherein the DSC thermogram of
form D has a further endothermic peak with an onset at
approximately 168-170.degree. C.
17. The polymorphic form of arformoterol tartrate form D according
to claim 1, which has a powder X-ray diffraction pattern further
comprising one or more additional peaks at 7.4, 15.9, 25.1 and
25.8.+-.0.2 degrees two theta.
18. The polymorphic form of arformoterol tartrate form D according
to claim 1, having a powder X-ray diffraction pattern in accordance
with FIG. 1.
19. The polymorphic form of arformoterol tartrate form D according
to claim 1, having at least 30% (w/w) of form D, preferably from
40% to 90% (w/w), more preferably from 50% to 80% (w/w) relative to
the total weight of form D and polymorph A.
20. The polymorphic form of arformoterol tartrate form D according
to claim 1, having between 40 and 50% of the known polymorph A.
21. A process for preparing arformoterol tartrate form D from
arformoterol base, the process comprising the steps of: a)
providing a mixture of arformoterol base with an alcohol, or with a
combination of acetonitrile and an alcohol, at a temperature
between 15 and 60.degree. C.; b) adding a solution of L-tartaric
acid in a solvent selected from an alcohol, water and mixtures
thereof, to the mixture obtained in step (a); c) cooling the
mixture of step (b) to a temperature between 30 and 15.degree. C.,
when necessary, followed by stirring to obtain a solid; d) further
cooling the mixture of step (c) to a temperature between 0 and
10.degree. C.; and e) collecting the crystals obtained in step (d),
and drying the crystals under inlet air pressure and at a
temperature between 30 and 50.degree. C. to yield arformoterol
tartrate form D.
22. The process according to the claim 21, wherein the mixture
provided in step (a) is a mixture of arformoterol base with an
alcohol, selected from methanol, ethanol, or isopropanol;
preferably methanol or ethanol; more preferably methanol.
23. The process according to claim 21, wherein the solution used in
step (b) is a solution of L-tartaric acid in an alcohol, selected
from methanol, ethanol, or isopropanol; preferably methanol or
ethanol; more preferably methanol.
24. The process according to the claim 21, wherein the alcohol used
in steps (a) and (b) is the same and is selected from methanol,
ethanol and isopropanol.
25. The process according to claim 24, wherein the preferred
alcohol used in step (a) and/or step (b) is methanol or
ethanol.
26. The process according to claim 21, wherein the ratio of the
alcohol/acetonitrile used in step (a) is of at least 1:0.1,
preferably between 1:1 and 1:5.
27. The process according to claim 21, wherein the mixture of step
(a) is preferably at a temperature between 20 and 60.degree. C.
28. The process according to claim 21, wherein the temperature of
the cooling carried out in step (d) is preferably between 0 and
5.degree. C.
29. A process for the preparation of a mixture of form D and
polymorph A of arformoterol tartrate, optionally from other
polymorphic forms of arformoterol tartrate, and comprising the
steps of: a) providing a mixture of arformoterol tartrate and a
solvent which is a mixture of an alcohol and water, at a
temperature between 60 and 70.degree. C.; b) cooling the mixture
obtained in step (a) to a temperature between 50 and 55.degree. C.;
c) adding acetonitrile to the mixture obtained in step (b) until a
suspension is obtained; d) cooling the suspension obtained in step
(c) while stirring to a temperature between 10 and 30.degree. C. to
obtain a solid; and e) collecting the crystals obtained in step (d)
and drying the crystals under vacuum at a pressure between 0.75 and
40 mm Hg and at a temperature between 50 and 90.degree. C.; wherein
the ratio of alcohol: water used in step (a) is over 1:1 and up to
5:1, wherein the mixture of form D and polymorph A of arformoterol
tartrate so prepared is according to claim 19.
30. A pharmaceutical composition comprising the arformoterol
tartrate according to claim 1 and at least one pharmaceutically
acceptable excipient or carrier.
31. A method of effecting bronchodilation, the method comprising
the administration, to a subject in need of such treatment, of a
therapeutically effective amount of arformoterol tartrate according
to claim 1.
32. A method of effecting bronchodilation, the method comprising
the administration, to a subject in need of such treatment, of a
pharmaceutical composition according to claim 19.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a new polymorphic form of a
long-acting beta-2 adrenoceptor agonist, arformoterol tartrate. In
addition, the invention relates to intermediates in the preparation
of the new polymorphic form, processes for obtaining the new
polymorphic form, and compositions and uses thereof.
BACKGROUND OF THE INVENTION
[0002] Formoterol,
(+/-)N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amin-
o]ethyl]phenyl]formamide, is a highly potent and
.beta..sub.2-selective adrenoceptor agonist having a long lasting
bronchodilating effect when inhaled. It is represented by the
following structural formula:
##STR00001##
[0003] Formoterol was first disclosed in Japanese patent
application 13121 (equivalent to U.S. Pat. No. 3,994,974), wherein
formoterol is synthesised by N-alkylation using a phenacyl
bromide.
[0004] Formoterol has two chiral centres, each of which can exist
in two different configurations. This results in four different
combinations: (R,R), (S,S), (S,R) and (R,S). Formoterol is
commercially available as a racemic mixture of 2 enantiomers (R,R)
and (S,S) in a 1:1 ratio. The generic name formoterol always refers
to its racemic mixture. Trofast et al. (Chirality, 1, 443, 1991)
reported on the potency of these isomers, showing a decrease in the
order of (R,R)>(R,S).gtoreq.(S,R)>(S,S). The (R,R) isomer,
also known as arformoterol, being 1000 fold more potent than the
(S,S) isomer.
[0005] Arformoterol is commercialised by Sepracor as a tartrate
salt under the brand name Brovana.RTM.. The chemical name for
arformoterol tartrate is
N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2(4-methoxyphenyl)-1-methyleth-
yl]amino]ethyl]phenyl]formamide, (2R,3R)-2,3-dihydroxybutanedioate
(1:1 salt), and it is represented by the following structural
formula:
##STR00002##
[0006] Various processes for the preparation of formoterol, its
enantiomers, related compounds, and their pharmaceutically
acceptable salts are disclosed in U.S. Pat. Nos. 3,994,974;
5,434,304; 6,268,533 and 6,472,563; Chem. Pharm. Bull. 26,
1123-1129 (1978); Chirality 3, 443-450 (1991); Drugs of the Future
2006, 31(11), 944-952; and WO 2008/035380A2. U.S. Pat. No.
6,268,533 describes salts of arformoterol and a method to produce
them; amongst these salts L-tartrate was used to produce
R,R-formoterol L-tartrate (hereinafter referred to as arformoterol
tartrate). U.S. Pat. No. 6,268,533 further discloses polymorphic
forms of arformoterol tartrate referred to as P1 and P2,
characterized by Differential Scanning calorimetry (DSC). Polymorph
P1 in pure form exhibits a peak at about 193.degree. C. on DSC and
a solubility in water at 25.degree. C. to the extent of 15.4 mg/mL.
Polymorph P2 in pure form exhibits a transition peak at about
179.degree. C. on DSC and a solubility in water at 25.degree. C. to
the extent of 26.7 mg/mL.
[0007] U.S. Pat. No. 6,472,563 discloses a further crystalline
polymorph of arformoterol tartrate, designated as "polymorph C",
and which is reported to be useful for the preparation of highly
pure "form A" of arformoterol. U.S. Pat. No. 6,472,563 renamed the
polymorphs P1 and P2 of U.S. Pat. No. 6,268,533 as "polymorph A"
(i.e. form A) and "polymorph B", respectively. The XRPD peaks and
the FTIR spectrum for the polymorphic forms A, B and C are also
disclosed in U.S. Pat. No. 6,472,563.
[0008] Polymorphs are different crystalline forms of the same pure
substance in which the molecules have different spatial
configurations relative to each other in the solid state. In
accordance with regulatory requirements of the U.S. and other
countries, e.g. the FDA's Good Manufacturing Practice ("GMP")
requirements, when preparing pharmaceutical compositions containing
active ingredients for administration to mammals, there is a need
to produce crystalline forms, or polymorphs, which are as pure and
as stable as possible. Differences in the chemical and physical
properties of polymorphic forms of an active ingredient such as
melting point, chemical reactivity and apparent solubility can have
a direct effect on the ability to process and/or manufacture the
active ingredient and its pharmaceutical compositions, as well as
on its stability, dissolution and bioavailability.
[0009] Arformoterol tartrate is commercialised as a sterile, clear
and colourless aqueous solution for inhalation. Therefore, it is
desirable to develop a pure and stable polymorphic form of
arformoterol tartrate, which shows reproducibly uniform crystalline
form and high solubility, which results in better properties for
use in pharmaceutical preparations, particularly in the preparation
of liquid pharmaceutical compositions. The preparation of new
polymorphic forms and solvates of pharmaceutically useful compounds
also provides a new opportunity to improve the performance
characteristics of pharmaceutical products and enlarges the
repertoire of materials that formulation scientists have available
for designing, for example, a pharmaceutical dosage form of a drug
with a targeted release profile or other desired
characteristic.
BRIEF DESCRIPTION OF THE INVENTION
[0010] Thus, in a first aspect of the present invention, there is
provided a new polymorphic form of arformoterol tartrate, referred
to as form D and defined as herein.
[0011] The inventors of the present invention have surprisingly
found that arformoterol tartrate can further exist in a new
polymorphic form, referred to herein as form D. The new form D
shows high purity, good stability and high solubility in water,
which makes it suitable for pharmaceutical formulation and in
particular for liquid pharmaceutical formulations
[0012] A second aspect of the present invention relates to a new
acetonitrile solvate of arformoterol tartrate. This may be used as
an intermediate in the preparation of arformoterol tartrate form
D.
[0013] A third aspect of the present invention relates to a process
for preparing the acetonitrile solvate of arformoterol tartrate of
the invention from other polymorphic forms of arformoterol tartrate
or mixtures thereof.
[0014] A fourth aspect of the present invention relates to a
process for preparing arformoterol tartrate form D, from the
acetonitrile solvate of arformoterol tartrate of the invention.
[0015] A fifth aspect of the present invention relates to a process
for preparing arformoterol tartrate form D, from other polymorphic
forms of arformoterol tartrate or mixtures thereof.
[0016] A sixth aspect of the present invention relates to a process
for preparing arformoterol tartrate form D, from arformoterol
base.
[0017] A seventh aspect of the present invention relates to the use
of the acetonitrile solvate of the invention in the preparation of
arformoterol tartrate form D.
[0018] An eighth aspect of the present invention relates to
mixtures of form D and polymorph A of arformoterol tartrate.
[0019] A ninth aspect of the present invention relates to a process
for the preparation of mixtures of form D and polymorph A of
arformoterol tartrate
[0020] A tenth aspect of the present invention relates to a
pharmaceutical composition comprising arformoterol tartrate form D,
or a mixture of form D and polymorph A of arformoterol tartrate,
and at least one pharmaceutically acceptable excipient. The
composition may be in liquid form (e.g. a solution or suspension),
or a solid form (e.g. powder for inhalation).
[0021] In compositions according to the tenth aspect and containing
a mixture of form D and polymorph A of arformoterol tartrate, the
composition may be such that the percentage by weight of form D is
at least 30% (w/w), preferably from 40% to 90% (w/w), more
preferably form 50% to 80% (w/w) relative to the total weight of
form D and polymorph A.
[0022] An eleventh aspect of the invention relates to arformoterol
tartrate form D, a mixture according to the eighth aspect; or a
pharmaceutical composition according to the tenth aspect, for use
in therapy. A twelfth aspect relates to form D, a mixture according
to the eighth aspect, or a pharmaceutical composition according to
the tenth aspect, for use as a bronchodilator.
[0023] A thirteenth aspect of the invention relates to a method of
effecting bronchodilation in a subject in need thereof, the method
comprising administering to the subject a therapeutically effective
amount of arformoterol tartrate form D, or a mixture of form D and
polymorph A of arformoterol tartrate, or a composition according to
the tenth aspect.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 shows the powder X-ray diffraction pattern (PXRD) of
polymorph D of arformoterol tartrate.
[0025] FIG. 2 shows the powder X-ray diffraction pattern (PXRD) of
the acetonitrile solvate of arformoterol tartrate of the
invention.
[0026] FIG. 3 shows the differential scanning calorimetry (DSC) and
the thermogravimetric analysis (TGA) results of arformoterol
tartrate form D, in a mixture containing between 40 and 50% of the
known polymorph A.
DEFINITIONS
[0027] The term "interplanar distance" as used herein (and referred
to as `d value`) refers to the spacing (in .ANG.) between the
planes in the arformoterol tartrate crystal lattice; "crystal
lattice" is defined as the array of periodic and repeating
arrangements of atoms that are found in crystalline solids.
[0028] The term "inlet air pressure" as used herein refers to the
pressure exerted by an input stream of air.
[0029] The term "particle size distribution" (or "PSD") as used
herein refers to the relative percentages by volume of each of the
different size fractions of a particulate matter. The particle size
distributions of the present application can be measured using
laser light diffraction equipment, such as a Malvern
Mastersizer.RTM. 2000. Particle size is determined by measuring the
angular distribution of laser light scattered by a homogeneous
suspension of particles. The size distribution is determined from
the light scattering data using the theory of light scattering
developed by Gustav Mie. Other types of equipment are also suitable
to determine particle size distribution. Laser light diffraction
results may be expressed by d.sub.10, d.sub.50, and/or d.sub.90
values, which are based on a volume distribution. The term "dx", as
used herein, means that x % of the particles in a composition
(based on volume) have a diameter equal to or below a specified d
value. For example, a d.sub.50 of 100 .mu.m means that 50% by
volume, of the particles, have a diameter equal to or below 100
.mu.m.
DETAILED DESCRIPTION OF THE INVENTION
[0030] According to the first aspect, the present invention relates
to a polymorphic form of arformoterol tartrate, referred to as form
D, and which is characterized by at least one of the following:
(i) a powder X-ray diffraction (PXRD) pattern having peaks at
approximately 6.8, 13.3, 13.6, 13.8, 14.1, 18.2, 18.7, 20.0.+-.0.2
degrees two theta (i.e. Bragg's angle); or (ii) a DSC thermogram
showing an endothermic peak with an onset at approximately
119-120.degree. C., and a maximum at approximately 129-131.degree.
C., followed by an exothermic peak with a maximum at approximately
137-138.degree. C.; wherein the DSC thermogram of form D has a
further endothermic peak with an onset at approximately
168-170.degree. C.
[0031] Arformoterol tartrate form D of the present invention can be
obtained in 100% ee (enantiomeric purity). Arformoterol tartrate
form D of the present invention shows a high chemical purity,
containing as low as 0.3% of total impurities, as determined by
HPLC. In addition, the arformoterol tartrate form D of the present
invention, contains an amount of the degradation impurity
(R)-1-(3-amino-4-hydroxyphenyl)-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethy-
l]amino]ethanol equal or less than 0.2%, as determined by HPLC.
Said arformoterol form D remains stable and shows no colour
variation under temperatures between 5 and 30.degree. C. and
atmospheric, vacuum or inert pressures. Said arformoterol tartrate
form D also remains polymorphically and chemically stable and shows
no colour variation after at least 6 months of storage under vacuum
at 25.degree. C..+-.2.degree. C. temperature and 60%.+-.5% Relative
Humidity (RH), and/or at 40.degree. C..+-.2.degree. C. temperature
and 75%.+-.5% Relative Humidity (RH). The present inventors have
also found that arformoterol tartrate form D does not show
polymorphic changes when subjected to grinding.
[0032] The arformoterol tartrate form D of the present invention
has a particle size distribution d.sub.50 equal to or less than 100
.mu.m, preferably less than 50 .mu.m, more preferably less than 20
.mu.m, still more preferably less than 10 .mu.m and most preferably
less than 5 .mu.m.
[0033] In a particular embodiment of the first aspect, the
arformoterol tartrate form D has a powder X-ray diffraction pattern
further comprising one or more additional peaks at approximately
7.4, 15.9, 25.1 and 25.8.+-.0.2 degrees two theta.
[0034] In one embodiment of the first aspect, the arformoterol
tartrate form D has a powder X-ray diffraction pattern,
characterised by the interplanar distance values shown below:
TABLE-US-00001 Angle 2.theta. (.degree.) (.+-.0.2) d value (.ANG.)
6.8 13.01 13.3 6.65 13.6 6.49 13.8 6.40 14.1 6.27 18.2 4.87 18.7
4.73 20.0 4.44
[0035] In a particular embodiment of the first aspect, the
arformoterol tartrate form D has a powder X-ray diffraction pattern
further comprising one or more additional interplanar distance
values shown below:
TABLE-US-00002 Angle 2.theta. (.degree.) (.+-.0.2) d value (.ANG.)
7.4 11.99 15.9 5.58 25.1 3.54 25.8 3.45
[0036] In one example of the first aspect, the PXRD pattern of the
arformoterol tartrate form D can be depicted substantially as in
FIG. 1.
[0037] In a particular embodiment of the first aspect, the
arformoterol tartrate form D of the present invention shows
substantially no weight loss before decomposition. Decomposition is
observed at temperatures over 167.degree. C.
[0038] In another particular embodiment of the first aspect, the
arformoterol tartrate form D of the present invention may contain
residual non-solvated acetonitrile in an amount equal to or less
than 1% (w/w), preferably in an amount equal to or less than 0.5%
(w/w), more preferably in an amount equal to or less than 0.2%
(w/w), even more preferably in an amount equal to or less than 0.1%
(w/w).
[0039] The arformoterol tartrate form D of the present invention
may exhibit a solubility in water, measured at 25 degrees C., of
between 38 and 83 mg/ml.
[0040] A second aspect of the present invention relates to an
acetonitrile solvate of arformoterol tartrate, characterised by at
least one of the following:
(i) a powder X-ray diffraction pattern showing the following peaks
at approximately 6.5, 13.7, 17.9, 18.4, 20.3, 21.6, 24.6 and
24.8.+-.0.2 degrees two theta; or (ii) a DSC thermogram showing an
endothermic peak with an onset at approximately 124-125.degree. C.,
and a maximum at approximately 134-136.degree. C., followed by an
exothermic peak with a maximum at approximately 140-141.degree. C.;
wherein the DSC thermogram of form D has a further endothermic peak
with an onset at approximately 170-172.degree. C.
[0041] The solvate of the second aspect may be used as an
intermediate in the preparation of arformoterol tartrate form
D.
[0042] In a particular embodiment of the second aspect, the
acetonitrile solvate of arformoterol tartrate has a powder X-ray
diffraction pattern further comprising one or more additional peaks
at approximately 13.2, 16.6, 19.2, 23.3, and 25.1.+-.0.2 degrees
two theta.
[0043] In one embodiment of the second aspect, the acetonitrile
solvate of arformoterol tartrate has a powder X-ray diffraction
pattern, characterised by the interplanar distance values shown
below:
TABLE-US-00003 Angle 2.theta. (.degree.) (.+-.0.2) d value (.ANG.)
6.5 13.66 13.7 6.46 17.9 4.95 18.4 4.81 20.3 4.37 21.6 4.10 24.6
3.62 24.8 3.59
[0044] In a particular embodiment of the second aspect, the
acetonitrile solvate of arformoterol tartrate has a powder X-ray
diffraction pattern further comprising one or more additional
interplanar distance values shown below:
TABLE-US-00004 Angle 2.theta. (.degree.) (.+-.0.2) d value (.ANG.)
13.2 6.72 16.6 5.32 19.2 4.62 23.3 3.82 25.1 3.54
[0045] In a preferred embodiment of the second aspect, the
acetonitrile solvate of arformoterol tartrate contains solvated
acetonitrile in an amount between 0.2 and 5% (w/w), preferably in
an amount between 1.6 and 4.1% (w/w), more preferably in an amount
between 2 and 4% (w/w). The acetonitrile solvate of arformoterol
tartrate may contain residual non-solvated acetonitrile in an
amount equal to or less than 1% (w/w), preferably in an amount
equal to or less than 0.5% (w/w), more preferably in an amount
equal to or less than 0.2% (w/w), even more preferably in an amount
equal to or less than 0.1% (w/w).
[0046] In one example of the second aspect, the PXRD pattern of the
acetonitrile solvate of arformoterol tartrate can be depicted
substantially as in FIG. 2.
[0047] A third aspect of the present invention relates to a process
for preparing the acetonitrile solvate of arformoterol tartrate of
the second aspect from other polymorphic forms of arformoterol
tartrate or mixtures thereof, the process comprising the steps of:
[0048] a) providing a mixture of arformoterol tartrate and a
solvent selected from an alcohol, water and mixtures thereof, at a
temperature between 60 and 70.degree. C.; [0049] b) cooling the
mixture obtained in step (a) to a temperature between 50 and
55.degree. C.; [0050] c) adding acetonitrile to the mixture
obtained in step (b) until a suspension is obtained; [0051] d)
cooling the suspension obtained in step (c) while stirring to a
temperature between 10 and 30.degree. C. to obtain a solid; and
[0052] e) collecting the crystals obtained in step (d) and drying
the crystals under vacuum at a pressure between 0.75 and 40 mm Hg
and at a temperature between 20 and 45.degree. C.; or drying the
crystals under inlet air pressure and at a temperature between 20
and 45.degree. C., to yield acetonitrile solvate of arformoterol
tartrate; wherein when the solvent used in step in step (a) is a
mixture of alcohol and water, the ratio of alcohol/water is between
1:1 and 1:9, preferably between 1:1 and 1:5, more preferably
between 1:2 and 1:4. [0053] In a preferred embodiment, the alcohol
used in step (a) is selected from methanol, ethanol and
isopropanol. In a more preferred embodiment, the alcohol is
methanol or ethanol.
[0054] In one embodiment of the third aspect, the arformoterol
tartrate provided in step (a) can comprise other polymorphic forms
(i.e. other than form D) of arformoterol tartrate and mixtures
thereof.
[0055] In another preferred embodiment of the third aspect, the
temperature of the mixture of step (a) is between 60 and 65.degree.
C.
[0056] In a preferred embodiment of the third aspect, the ratio of
solvent used in step (a) to the acetonitrile used in step (c) is at
least 1:1, preferably between 1:1 and 1:5, more preferably between
1:2 and 1:4. The ratio of solvent in step (a) to acetonitrile is
not critical, although it is preferred that the amount of
acetonitrile is greater than the amount of solvent.
[0057] In a preferred embodiment of the third aspect, the steps (a)
to (d) are performed under inert atmosphere, such as under nitrogen
or argon atmosphere. Preferably, they are performed under nitrogen
atmosphere.
[0058] In a particular embodiment of the third aspect, the drying
of step (e) is carried out at a pressure that ranges between 0.75
and 40 mm Hg, preferably between 0.75 and 20 mm Hg, more preferably
between 0.75 and 3 mm Hg, most preferably between 1.5 and 2.25 mm
Hg; and at a controlled temperature between 20 and 45.degree. C.,
preferably between 25 and 40.degree. C., more preferably between 30
and 40.degree. C. In another embodiment, the drying of step (e) is
carried out under inlet air pressure (atmospheric pressure); and at
a controlled temperature between 20 and 45.degree. C., preferably
between 25 and 40.degree. C., more preferably between 30 and
40.degree. C.
[0059] In a more preferred embodiment of the third aspect of the
present invention, the process for preparing the acetonitrile
solvate of arformoterol tartrate of the second aspect from other
polymorphic forms of arformoterol tartrate or mixtures thereof
comprises the steps of: [0060] a) providing a mixture of
arformoterol tartrate and an alcohol, at a temperature between 60
and 70.degree. C.; [0061] b) cooling the mixture obtained in step
(a) to a temperature between 50 and 55.degree. C.; [0062] c) adding
acetonitrile to the mixture obtained in step (b) until a suspension
is obtained; [0063] d) cooling the suspension obtained in step (c)
while stirring to a temperature between 10 and 30.degree. C. to
obtain a solid; and [0064] e) collecting the crystals obtained in
step (d) and drying the crystals under vacuum at a pressure between
0.75 and 40 mm Hg and at a temperature between 20 and 45.degree.
C.; or drying the crystals under inlet air pressure and at a
temperature between 20 and 45.degree. C., to yield acetonitrile
solvate of arformoterol tartrate; wherein the alcohol used in step
in step (a) is selected from methanol, ethanol and isopropanol,
preferably methanol or ethanol
[0065] The method according to the third aspect of the present
invention is simple, and permits to be obtained an acetonitrile
solvate of arformoterol tartrate, which can be used as an
intermediate in the preparation of the new arformoterol tartrate
form D. Said form D shows a high chemical purity (the level of
total impurities is as low as 0.3%, as determined by HPLC), remains
stable and shows no colour variation under temperatures between 5
and 30.degree. C. and atmospheric, vacuum or inert pressures. Said
arformoterol tartrate form D also remains polymorphically and
chemically stable and shows no colour variation after at least 6
months of storage under vacuum at 25.degree. C..+-.2.degree. C.
temperature and 60%.+-.5% Relative Humidity (RH), and/or at
40.degree. C..+-.2.degree. C. temperature and 75%.+-.5% Relative
Humidity (RH).
[0066] A fourth aspect of the present invention relates to a
process for preparing the arformoterol tartrate form D of the first
aspect, from the acetonitrile solvate of arformoterol tartrate of
the second aspect, comprising the step of drying the crystals of
acetonitrile solvate of arformoterol tartrate, obtained for example
as disclosed in the third aspect of the present invention, under
inlet air pressure (atmospheric pressure) or under vacuum at a
pressure between 0.75 and 40 mm Hg, and at a temperature between 50
and 90.degree. C.
[0067] As described in the third aspect, the ratio of alcohol/water
used in step (a) thereof, when the solvent used in said step is a
mixture of alcohol and water, is between 1:1 and 1:9, preferably
between 1:1 and 1:5, more preferably between 1:2 and 1:4. The ratio
of alcohol/water between 1:1 and 1:9 leads towards the formation of
form D. As the ratio of alcohol to water increases over 1:1 (i.e.
the amount of alcohol is greater than the amount of water),
mixtures of form D and form A are obtained.
[0068] In a particular embodiment of the fourth aspect, the
pressure applied during drying, ranges between 0.75 and 40 mm Hg,
preferably between 0.75 and 20 mm Hg, more preferably between 0.75
and 3 mm Hg, most preferably between 1.5 and 2.25 mm Hg. In another
embodiment, the drying of step (e) is carried out under inlet air
pressure (atmospheric pressure).
[0069] In a preferred embodiment of the fourth aspect, the drying
is carried out at a temperature between 60 and 80.degree. C. In a
more preferred embodiment, the temperature is 80.degree. C.
[0070] The method according to the fourth aspect of the present
invention is simple, and permits the end product (arformoterol
tartrate form D) to be obtained in a high chemical purity (the
level of total impurities is as low as 0.3%, as determined by
HPLC). In addition, the arformoterol tartrate form D obtained
according the fourth aspect of the present invention, contains an
amount of the degradation impurity
(R)-1-(3-amino-4-hydroxyphenyl)-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethy-
l]amino]ethanol equal or less than 0.2%, as determined by HPLC.
Said arformoterol tartrate form D remains stable and shows no
colour variation under temperatures between 5 and 30.degree. C. and
atmospheric, vacuum or inert pressures. The inventors of the
present invention have also found that arformoterol tartrate form D
does not show polymorphic changes when subjected to grinding. Said
arformoterol tartrate form D also remains polymorphically and
chemically stable and shows no colour variation after at least 6
months of storage under vacuum at 25.degree. C..+-.2.degree. C.
temperature and 60%.+-.5% Relative Humidity (RH), and/or at
40.degree. C..+-.2.degree. C. temperature and 75%.+-.5% Relative
Humidity (RH).
[0071] In a similar way as in the fourth aspect, the arformoterol
tartrate form D of the present invention can be obtained from other
solvates of arformoterol tartrate such as ethyl acetate, acetone,
dichloromethane, tetrahydrofuran, methylsulfoxide,
dimethylformamide or toluene solvate; preferably ethyl acetate
solvate or tetrahydrofuran solvate. Said solvates of arformoterol
tartrate can be prepared following the procedure described in the
third aspect of the present invention, with the only difference
that ethyl acetate or tetrahydrofuran is added in step (c) instead
of acetonitrile.
[0072] A fifth aspect of the present invention relates to a process
for preparing the arformoterol tartrate form D of the first aspect
from other polymorphic forms of arformoterol tartrate or mixtures
thereof, the process comprising the steps of: [0073] a) providing a
mixture of arformoterol tartrate and a solvent selected from an
alcohol, water and mixtures thereof, at temperature between 60 and
70.degree. C.; [0074] b) cooling the mixture obtained in step (a)
to a temperature between 50 and 55.degree. C.; [0075] c) adding
acetonitrile to the mixture obtained in step (b) until a suspension
is obtained; [0076] d) cooling the suspension obtained in step (c)
while stirring to a temperature between 10 and 30.degree. C. to
obtain a solid; and [0077] e) collecting the crystals obtained in
step (d), and drying the crystals under vacuum at a pressure
between 0.75 and 40 mm Hg and at a temperature between 50 and
90.degree. C., to yield arformoterol tartrate form D; wherein when
the solvent used in step in step (a) is a mixture of alcohol and
water, the ratio of alcohol/water is between 1:1 and 1:9,
preferably between 1:1 and 1:5, more preferably between 1:2 and
1:4.
[0078] The ratio of alcohol/water between 1:1 and 1:9 leads towards
the formation of form D. As the ratio of alcohol to water increases
over 1:1 (i.e. the amount of alcohol is greater than the amount of
water), mixtures of form D and form A are obtained. In a preferred
embodiment, the alcohol used in step (a) is selected from methanol,
ethanol and isopropanol. In a more preferred embodiment, the
alcohol is methanol or ethanol.
[0079] In one embodiment of the fifth aspect, the arformoterol
tartrate provided in step (a) can comprise other polymorphic forms
(i.e. other than form D) of arformoterol tartrate and mixtures
thereof.
[0080] In another preferred embodiment of the fifth aspect, the
temperature of the mixture of step (a) is between 60 and 65.degree.
C.
[0081] In a preferred embodiment of the fifth aspect, the ratio of
solvent used in step (a) to the acetonitrile used in step (c) is at
least 1:1, preferably between 1:1 and 1:5, more preferably between
1:2 and 1:4. The ratio of solvent in step (a) to acetonitrile of
step (c) is not critical, although it is preferred that the amount
of acetonitrile is greater than the amount of solvent, since it
allows obtaining arformoterol tartrate form D having better
yields.
[0082] In another preferred embodiment of the fifth aspect, the
mixture of step (b) is seeded with arformoterol tartrate form D
once the acetonitrile of step (c) is added.
[0083] In a preferred embodiment of the fifth aspect, the steps (a)
to (d) are performed under inert atmosphere, such as under nitrogen
or argon atmosphere. Preferably, they are performed under nitrogen
atmosphere.
[0084] In a particular embodiment of the fifth aspect, the crystals
obtained in step (d) may be further purified, prior to the drying
of step (e). In a preferred embodiment, the purification is carried
out by crystallization from a single solvent or a combination of
solvents, selected from methanol, ethanol and isopropanol;
preferably methanol and/or ethanol; more preferably methanol. The
crystallization can be carried out more than once, if necessary.
Said crystallization may be preferably performed under inert
atmosphere, such as under nitrogen or argon atmosphere.
[0085] In a particular embodiment, the drying of step (e) is
carried out at a pressure that ranges between 0.75 and 40 mm Hg,
preferably between 0.75 and 20 mm Hg, more preferably between 0.75
and 3 mm Hg, most preferably between 1.5 and 2.25 mm Hg; and at a
controlled temperature between 50 and 90.degree. C., preferably
between 60 and 80.degree. C., more preferably at 80.degree. C.
[0086] In a more preferred embodiment of the fifth aspect of the
present invention, the process for preparing the acetonitrile
solvate of arformoterol tartrate of the second aspect from other
polymorphic forms of arformoterol tartrate or mixtures thereof
comprises the steps of: [0087] a) providing a mixture of
arformoterol tartrate and an alcohol at a temperature between 60
and 70.degree. C.; [0088] b) cooling the mixture obtained in step
(a) to a temperature between 50 and 55.degree. C.; [0089] c) adding
acetonitrile to the mixture obtained in step (b) until a suspension
is obtained; [0090] d) cooling the suspension obtained in step (c)
while stirring to a temperature between 10 and 30.degree. C. to
obtain a solid; and [0091] e) collecting the crystals obtained in
step (d), and drying the crystals under vacuum at a pressure
between 0.75 and 40 mm Hg and at a temperature between 50 and
90.degree. C., to yield arformoterol tartrate form D; wherein the
alcohol used in step (a) is selected from methanol, ethanol and
isopropanol, preferably methanol or ethanol.
[0092] The method according to the fifth aspect of the present
invention is simple, and permits the end product (arformoterol
tartrate form D) to be obtained in a high chemical purity (the
level of total impurities is as low as 0.3%, as determined by
HPLC). In addition, the arformoterol tartrate form D obtained
according the fifth aspect of the present invention, contains an
amount of the degradation impurity
(R)-1-(3-amino-4-hydroxyphenyl)-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethy-
l]amino]ethanol equal or less than 0.2%, as determined by HPLC.
Said arformoterol tartrate form D remains stable and shows no
colour variation at ambient conditions, under temperatures between
5 and 30.degree. C. and atmospheric, vacuum or inert pressures. The
inventors of the present invention have also found that
arformoterol tartrate form D does not show polymorphic changes when
grinded. Said arformoterol tartrate form D also remains
polymorphically and chemically stable and shows no colour variation
after at least 6 months of storage under vacuum at 25.degree.
C..+-.2.degree. C. temperature and 60%.+-.5% Relative Humidity
(RH), and/or at 40.degree. C..+-.2.degree. C. temperature and
75%.+-.5% Relative Humidity (RH).
[0093] A sixth aspect of the present invention relates to a process
for preparing the arformoterol tartrate form D of the first aspect
from arformoterol base, the process comprising the steps of: [0094]
a) providing a mixture of arformoterol base with an alcohol, or
with a combination of acetonitrile and an alcohol, at a temperature
between 15 and 60.degree. C.; [0095] b) adding a solution of
L-tartaric acid in a solvent selected from an alcohol, water and
mixtures thereof, to the mixture obtained in step (a); [0096] c)
cooling the mixture of step (b), when necessary, to a temperature
between 30 and 15.degree. C. followed by stirring to obtain a
solid; [0097] d) further cooling the mixture of step (c) to a
temperature between 0 and 10.degree. C.; and [0098] e) collecting
the crystals obtained in step (d), and drying the crystals under
inlet air pressure and at a temperature between 30 and 50.degree.
C. to yield arformoterol tartrate form D.
[0099] In a preferred embodiment, the alcohol used in steps (a) and
(b) is the same and is selected from methanol, ethanol and
isopropanol. In a more preferred embodiment, the alcohol is
methanol or ethanol. In the most preferred embodiment, the alcohol
is methanol.
[0100] In another preferred embodiment of the sixth aspect, the
mixture provided in step (a) is a mixture of arformoterol base with
an alcohol and the solution used in step (b) is a solution of
L-tartaric acid in an alcohol. In a more preferred embodiment, said
alcohol used in steps (a) and (b) is the same and is selected from
methanol, ethanol and isopropanol, preferably form methanol or
ethanol, more preferably is methanol. The use of alcohol in steps
(a) and (b) allows obtaining arformoterol tartrate form D having
good yield and HPLC purity without the need to use
acetonitrile.
[0101] The ratio of alcohol/acetonitrile used in step (a), when a
combination of an alcohol and acetonitrile is used, is preferably
between 1:0.1 and 1:5, more preferably between 1:1 and 1:4.
[0102] In another preferred embodiment, the mixture of step (a) is
preferably at a temperature between 20 and 60.degree. C.
[0103] In another preferred embodiment of the sixth aspect, the
mixture of step (b) is seeded with arformoterol tartrate form D
once the acetonitrile of step (c) is added.
[0104] In another preferred embodiment of the sixth aspect, the
temperature of the cooling carried out in step (d) is preferably
between 0 and 5.degree. C.
[0105] In a preferred embodiment of the sixth aspect, the steps (a)
to (d) are performed under inert atmosphere, such as under nitrogen
or argon atmosphere. Preferably, they are performed under nitrogen
atmosphere.
[0106] In a particular embodiment of the sixth aspect, the crystals
obtained in step (d) may be further purified, previous to the
drying of step (e). In a preferred embodiment, the purification is
carried out by crystallization from a single solvent or a
combination of solvents, selected from methanol, ethanol and
isopropanol; preferably methanol and/or ethanol; more preferably
methanol. The crystallization can be carried out more than once, if
necessary. Said crystallization may be preferably performed under
inert atmosphere, such as under nitrogen or argon atmosphere.
[0107] In a preferred embodiment of the sixth aspect, the drying of
step (e) is carried out under inlet air pressure (atmospheric
pressure); and at a controlled temperature between 30 and
50.degree. C., preferably between 35 and 45.degree. C., more
preferably at 40.degree. C. In another embodiment, the drying of
step (e) is performed at a pressure between 0.75 and 40 mm Hg,
without the use of inlet air pressure; and at a controlled
temperature between 30 and 50.degree. C., preferably between 35 and
45.degree. C., more preferably at 40.degree. C.
[0108] In a more preferred embodiment of the sixth aspect of the
present invention, the process for preparing the arformoterol
tartrate form D of the first aspect from arformoterol base
comprises the steps of: [0109] a) providing a mixture of
arformoterol base with an alcohol, at a temperature between 15 and
60.degree. C.; [0110] b) adding a solution of L-tartaric acid in an
alcohol, to the mixture obtained in step (a); [0111] c) cooling the
mixture of step (b) to a temperature between 30 and 15.degree. C.,
when necessary, followed by stirring to obtain a solid; [0112] d)
further cooling the mixture of step (c) to a temperature between 0
and 10.degree. C.; and [0113] e) collecting the crystals obtained
in step (d), and drying the crystals under inlet air pressure and
at a temperature between 30 and 50.degree. C. to yield arformoterol
tartrate form D; wherein the alcohol used in step (a) and (b) is
selected from methanol, ethanol, or isopropanol, preferably
methanol or ethanol, more preferably methanol.
[0114] In a more preferred embodiment of the sixth aspect of the
present invention, the process for preparing the arformoterol
tartrate form D of the first aspect from arformoterol base
comprises the steps of: [0115] a) providing a mixture of
arformoterol base with an alcohol, at a temperature between 15 and
60.degree. C.; [0116] b) adding a solution of L-tartaric acid in an
alcohol, to the mixture obtained in step (a); [0117] c) cooling the
mixture of step (b), when necessary, to a temperature between 30
and 15.degree. C. followed by stirring to obtain a solid; [0118] d)
further cooling the mixture of step (c) to a temperature between 0
and 5.degree. C.; and [0119] e) collecting the crystals obtained in
step (d), and drying the crystals under inlet air pressure and at a
temperature between 30 and 50.degree. C. to yield arformoterol
tartrate form D; wherein the alcohol used in step (a) and (b) is
selected from methanol, ethanol, or isopropanol, preferably
methanol or ethanol, more preferably methanol; and the steps (a) to
(d) are performed under inert atmosphere, such as under nitrogen or
argon atmosphere.
[0120] The method according to the sixth aspect of the present
invention is simple, and permits the end product (arformoterol
tartrate form D) to be obtained in a high chemical purity (the
level of total impurities is as low as 0.3%). In addition, the
arformoterol tartrate form D obtained according the sixth aspect of
the present invention, contains an amount of the degradation
impurity
(R)-1-(3-amino-4-hydroxyphenyl)-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethy-
l]amino]ethanol equal or less than 0.2%, as determined by HPLC.
Said arformoterol tartrate form D remains stable and shows no
colour variation under temperatures between 5 and 30.degree. C. and
atmospheric, vacuum or inert pressures. The inventors of the
present invention have also found that arformoterol tartrate form D
does not show polymorphic changes when grinded. Said arformoterol
tartrate form D also remains polymorphically and chemically stable
and shows no colour variation after at least 6 months of storage
under vacuum at 25.degree. C..+-.2.degree. C. temperature and
60%.+-.5% Relative Humidity (RH), and/or at 40.degree.
C..+-.2.degree. C. temperature and 75%.+-.5% Relative Humidity
(RH).
[0121] The crystalline solid arformoterol tartrate obtained or
obtainable according to any of the processes described in the
fourth, fifth or sixth aspect is a highly pure arformoterol
tartrate characterised in that it contains less than 0.5% of total
chemical impurities, based on the total weight of the crystalline
solid. Additionally, the crystalline solid arformoterol tartrate
obtained or obtainable according to any of the processes described
in the fourth, fifth or sixth aspect is a highly pure arformoterol
tartrate characterised in that it contains less than equal or less
than 0.2% of the degradation impurity
(R)-1-(3-amino-4-hydroxyphenyl)-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethy-
l]amino]ethanol) based on the total weight of the crystalline
solid. Said crystalline arformoterol tartrate Form D is also
characterized by having high polymorphic and chemical stability
over time, remaining at least 95%, preferably more than 97%, more
preferably more than 99%, in the polymorph Form D; and keeping the
levels of total chemical impurities lower than 0.5% (containing an
amount of the degradation impurity
(R)-1-(3-amino-4-hydroxyphenyl)-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethy-
l]amino]ethanol equal or less than 0.2%), after at least 6 months
of storage under vacuum at 25.degree. C..+-.2.degree. C.
temperature and 60%.+-.5% Relative Humidity (RH), and/or at
40.degree. C..+-.2.degree. C. temperature and 75%.+-.5% Relative
Humidity (RH).
[0122] A seventh aspect of the present invention relates to the use
of the acetonitrile solvate of the second aspect, in the
preparation of arformoterol tartrate form D of the first
aspect.
[0123] An eighth aspect of the present invention relates to a
mixture of form D and polymorph A of arformoterol tartrate.
[0124] In a preferred embodiment of the eighth aspect, the mixtures
of the invention comprise polymorph A and form D in quantities such
that the percentage by weight of form D is at least 30% (w/w),
preferably from 40% to 90% (w/w), more preferably form 50% to 80%
(w/w), relative to the total weight of form D and polymorph A.
[0125] In one embodiment of the eighth aspect, said mixtures of the
arformoterol tartrate form D and the known polymorph A of
arformoterol tartrate is characterised by a DSC thermogram showing
a first endothermic peak with an onset at approximately
123-125.degree. C. and a maximum at approximately 130-131.degree.
C.; followed by an exothermic peak with a maximum of approximately
137-138.degree. C.; and a second endothermic peak with a maximum at
approximately 191-192.degree. C., a characteristic from known
polymorph A.
[0126] In one example of the eighth aspect, the differential
scanning calorimetry (DSC) and the thermogravimetric analysis (TGA)
results of the mixtures of arformoterol tartrate form D having
between 40 and 50% of the known polymorph A can be depicted
substantially as in FIG. 3.
[0127] The physical properties of the two separate polymorphs (form
D and form A) were compared to the physical properties of mixtures
of the invention. It was discovered that polymorphic mixtures with
different polymorphic compositions have practically invariable
physical properties, in particular thermal characteristics, as
compared to the separate polymorphs (form A and form D). Hence,
even if there is polymorphic transformation, the thermal
characteristics of the polymorphic mixture may remain substantially
the same, which is ideal for formulation.
[0128] A ninth aspect of the present invention relates to a process
for the preparation of mixtures of form D and polymorph A of
arformoterol tartrate of the eighth aspect, comprising the steps
of: [0129] a) providing a mixture of arformoterol tartrate and a
solvent which is a mixture of an alcohol and water, at a
temperature between 60 and 70.degree. C.; [0130] b) cooling the
mixture obtained in step (a) to a temperature between 50 and
55.degree. C.; [0131] c) adding acetonitrile to the mixture
obtained in step (b) until a suspension is obtained; [0132] d)
cooling the suspension obtained in step (c) while stirring to a
temperature between 10 and 30.degree. C. to obtain a solid; and
[0133] e) collecting the crystals obtained in step (d) and drying
the crystals under vacuum at a pressure between 0.75 and 40 mm Hg
and at a temperature between 50 and 90.degree. C.; wherein the
ratio of alcohol: water used in step (a) is over 1:1 and up to 5:1,
preferably between 2:1 and 4:1, more preferably 3:1 and 4:1. As
previously described for the third aspect, the ratio of
alcohol/water between 1:1 and 1:9 leads to the formation of form D
instead of form A. As the ratio of alcohol to water increases over
1:1, mixtures of form D and form A are obtained. In a preferred
embodiment, the alcohol used in step (a) is selected from methanol
and ethanol.
[0134] In one embodiment of the ninth aspect, the arformoterol
tartrate of step (a) can be crystallised from other polymorphic
forms of arformoterol tartrate (i.e. other than form D) and
mixtures thereof.
[0135] In another preferred embodiment of the ninth aspect, the
temperature of the mixture of step (a) is between 60 and 65.degree.
C.
[0136] In a preferred embodiment of the ninth aspect, the ratio of
solvent used in step (a) to the acetonitrile used in step (c) is at
least 1:1, preferably between 1:1 and 1:5, more preferably between
1:1 and 1:4, most preferably between 1:2 and 1:3. The ratio of
solvent in step (a) to acetonitrile of step (c) is not critical,
although it is preferred that, when used, the amount of
acetonitrile is greater than the amount of solvent, since it allows
obtaining mixtures of form D and polymorph A of arformoterol
tartrate having good yields.
[0137] In a preferred embodiment of the ninth aspect, the steps (a)
to (d) are performed under inert atmosphere, such as under nitrogen
or argon atmosphere. Preferably, they are performed under nitrogen
atmosphere.
[0138] In a particular embodiment of the ninth aspect, the crystals
obtained in step (d) may be further purified, previous to the
drying of step (e). In a preferred embodiment, the purification is
carried out by crystallization from a single solvent or combination
of solvents, selected from methanol, ethanol and isopropanol;
preferably methanol and/or ethanol; more preferably methanol. The
crystallization can be carried out more than once, if necessary.
Said crystallization may be preferably performed under inert
atmosphere, such as under nitrogen or argon atmosphere.
[0139] In a particular embodiment, the drying of step (e) is
carried out at a pressure that ranges between 0.75 and 40 mm Hg,
preferably between 0.75 and 20 mm Hg, more preferably between 0.75
and 3 mm Hg; and at a controlled temperature between 50 and
90.degree. C., preferably between 60 and 80.degree. C.
[0140] The method according to the ninth aspect of the present
invention is simple, and permits to obtain mixtures of the form D
and the known polymorph A of arformoterol tartrate in a high
chemical purity (the level of total impurities is as low as 0.3%,
as determined by HPLC).
[0141] The arformoterol tartrate obtained or obtainable according
to any of the processes described in the fourth, fifth, sixth or
ninth aspect has a particle size distribution d.sub.50 equal to or
less than 100 .mu.m, preferably less than 50 .mu.m, more preferably
less than 20 .mu.m, still more preferably less than 10 .mu.m and
most preferably less than 5 .mu.m.
[0142] A tenth aspect of the present invention relates to a
pharmaceutical composition comprising arformoterol tartrate form D,
or a mixture of form D and polymorph A of arformoterol tartrate,
and at least one pharmaceutically acceptable excipient. The
composition may be in liquid form (e.g. a solution or suspension),
or a solid form (e.g. powder for inhalation).
[0143] In compositions according to the tenth aspect and containing
a mixture of form D and polymorph A of arformoterol tartrate, the
composition may be such that the percentage by weight of form D is
at least 30% (w/w), preferably from 40% to 90% (w/w), more
preferably form 50% to 80% (w/w) relative to the total weight of
form D and polymorph A.
[0144] An eleventh aspect of the invention relates to arformoterol
tartrate form D, a mixture according to the eighth aspect, or a
pharmaceutical composition according to the tenth aspect, for use
in therapy.
[0145] A twelfth aspect relates to form D, a mixture according to
the eighth aspect, or a pharmaceutical composition according to the
tenth aspect, for use as a bronchodilator.
[0146] A thirteenth aspect of the invention relates to a method of
effecting bronchodilation in a subject in need thereof, the method
comprising administering to the subject a therapeutically effective
amount of arformoterol tartrate form D, or a mixture of form D and
polymorph A of arformoterol tartrate, or a pharmaceutical
composition according to the tenth aspect.
[0147] Pharmaceutical compositions of the present invention can be
in liquid form or in solid form. Arformoterol is commercialized as
a solution for inhalation packaged in 2.1 mL unit-dose, low-density
polyethylene (LDPE) unit-dose vials. Each unit-dose vial contains
15 mcg of arformoterol (equivalent to 22 mcg of arformoterol
tartrate) in a sterile, isotonic saline solution, and additional
excipients of a standard nature for such compositions.
[0148] Solid pharmaceutical compositions may typically be
appropriate when combining arformoterol tartrate with other active
ingredients, such as an inhaled corticosteroid, such as
ciclesonide. Form D of arformoterol tartrate or form D/polymorph A
mixtures (as described above) are also useful for the preparation
of such solid pharmaceutical compositions.
[0149] It is to be understood that, where preferred features are
presented above in relation to a particular aspect of the
invention, those features may also be preferred in other aspects of
the invention, as appropriate.
Further aspects/embodiments of the present invention can be found
in the following clauses: 1. A polymorphic form of arformoterol
tartrate, designated as form D, which is characterised by at least
one of the following: (i) a powder X-ray diffraction pattern having
peaks at approximately 6.8, 13.3, 13.6, 13.8, 14.1, 18.2, 18.7,
20.0.+-.0.2 degrees two theta; or (ii) a DSC thermogram showing an
endothermic peak with an onset at approximately 119-120.degree. C.,
and a maximum at approximately 129-131.degree. C., followed by an
exothermic peak with a maximum at approximately 137-138.degree. C.;
wherein the DSC thermogram of form D has a further endothermic peak
with an onset at approximately 168-170.degree. C. 2. The polymorph
of arformoterol tartrate according to clause 1, wherein the powder
X-ray diffraction pattern comprises interplanar distance values at
approximately 13.01, 6.65, 6.49, 6.40, 6.27, 4.87, 4.73 and 4.44
.ANG.. 3. The polymorph of arformoterol tartrate according to any
of the preceding clauses, wherein the powder X-ray diffraction
pattern further comprises one or more additional peaks at about
7.4, 15.9, 25.1 and 25.8.+-.0.2 degrees two theta. 4. The polymorph
of arformoterol tartrate according to any of the preceding clauses,
wherein the powder X-ray diffraction pattern further comprises one
or more interplanar distance values at approximately 11.99, 5.58,
3.54 and 3.45 .ANG.. 5. The polymorph of arformoterol tartrate
according to any of the preceding clauses, having a powder X-ray
diffraction pattern in accordance with FIG. 1. 6. The polymorph of
arformoterol tartrate according to any of the preceding clauses,
showing no weight loss before decomposition which is observed at
temperatures over 167.degree. C. 7. The polymorph of arformoterol
tartrate according to any of the preceding clauses characterised in
that it contains less than 0.5% of total chemical impurities based
on the total weight of the compound. 8. The polymorph of
arformoterol tartrate according to any of the preceding clauses,
characterised in that it contains equal or less than 0.2% of the
degradation impurity
(R)-1-(3-amino-4-hydroxyphenyl)-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethy-
l]amino]ethanol) based on the total weight of the compound. 9. An
acetonitrile solvate of arformoterol tartrate characterised by at
least one of the following: (i) a powder X-ray diffraction pattern
showing the following peaks at approximately 6.5, 13.7, 17.9, 18.4,
20.3, 21.6, 24.6 and 24.8.+-.0.2 degrees two theta; or (ii) a DSC
thermogram showing an endothermic peak with an onset at
approximately 124-125.degree. C., and a maximum at approximately
134-136.degree. C., followed by an exothermic peak with a maximum
at approximately 140-141.degree. C.; wherein the DSC thermogram of
form D has a further endothermic peak with an onset at
approximately 170-172.degree. C. 10. The acetonitrile solvate of
arformoterol tartrate according to clause 9, wherein the powder
X-ray diffraction pattern comprises interplanar distance values at
approximately 13.66, 6.46, 4.95, 4.81, 4.37, 4.10, 3.62 and 3.59
.ANG.. 11. The acetonitrile solvate of arformoterol tartrate
according to any of the clauses 9 to 10, wherein the powder X-ray
diffraction pattern further comprises one or more additional peaks
at about 13.2, 16.6, 19.2, 23.3, and 25.1.+-.0.2 degrees two theta.
12. The acetonitrile solvate of arformoterol tartrate according to
any of clauses 9 to 11, wherein the powder X-ray diffraction
pattern further comprises one or more interplanar distance values
at approximately 6.72, 5.32, 4.62, 3.82 and 3.54 .ANG.. 13. The
acetonitrile solvate of arformoterol tartrate according to any of
clauses 9 to 12, having a powder X-ray diffraction pattern in
accordance with FIG. 2. 14. The acetonitrile solvate of
arformoterol tartrate according to any of clauses 9 to 13, which
contains an amount of acetonitrile in a range between 0.2 and 5%
(w/w), preferably in an amount between 1.6 and 4.1% (w/w), more
preferably in an amount between 2 and 4% (w/w). 15. Use of the
acetonitrile solvate of arformoterol according to any of clauses 9
to 14, as an intermediate in the preparation of the form D of
arformoterol tartrate of clauses 1 to 6. 16. A process for
preparing acetonitrile solvate of arformoterol tartrate, as defined
in any of the clauses 9 to 14, from other polymorphic forms of
arformoterol tartrate comprising the steps of: [0150] a) providing
a mixture of arformoterol tartrate and a solvent selected from and
alcohol, water and mixtures thereof, at temperature between 60 and
70.degree. C.; [0151] b) cooling the mixture obtained in step (a)
to a temperature between 50 and 55.degree. C.; [0152] c) adding
acetonitrile to the mixture obtained in step (b) until a suspension
is obtained; [0153] d) cooling the suspension obtained in step (c)
while stirring to a temperature between 10 and 30.degree. C. to
obtain a solid; and [0154] e) collecting the crystals obtained in
step (d) and drying the crystals under vacuum at a pressure between
at a pressure between 0.75 and 40 mm Hg; and at a temperature
between 20 and 45.degree. C. to yield acetonitrile solvate of
arformoterol tartrate; [0155] wherein when the solvent used in step
in step (a) is a mixture of alcohol and water, the ratio of
alcohol: water is between 1:1 and 1:9. 17. The process according to
clause 16, wherein the alcohol used in step (a) is preferably
selected from methanol, ethanol and isopropanol. 18. The process
according to the preceding clause, wherein the preferred alcohol
used in step (a) is methanol or ethanol. 19. The process according
to any of the clauses 16 to 18 wherein the solvent of step (a) is a
mixture of alcohol/water in a ratio between 1:1 and 1:5. 20. The
process according to the preceding clause, wherein the ratio of the
mixture of alcohol/water is preferably between 1:1 and 1:4. 21. The
process according to any of clauses 16 to 20, wherein the
temperature of the mixture of step (a) is preferably between 60 and
65.degree. C. 22. The process according to any of the clauses 16 to
21, wherein the ratio of the solvent used in step (a) and the
acetonitrile used in step (c) is of at least 1:1, preferably
between 1:1 and 1:5. 23. The process according to the preceding
clause, wherein the ratio the solvent used in step (a) and the
acetonitrile used in step (c) is preferably between 1:2 and 1:4.
24. The process according to any of the clauses 16 to 23, wherein
the drying carried out in step (e) is performed at a pressure
between 0.75 and 40 mm Hg, preferably between 0.75 and 20 mm Hg,
more preferably between 0.75 and 3 mm Hg, most preferably between
1.5 and 2.25 mm Hg. 25. The process according to any of the clauses
16 to 24, wherein the drying carried out in step (e) is preferably
performed at a temperature between 25 and 40.degree. C., more
preferably between 30 and 40.degree. C. 26. A process for preparing
arformoterol tartrate form D, as defined in any of the clauses 1 to
6, comprising the step of drying crystals of acetonitrile solvate
of arformoterol tartrate, as defined in any of the clauses 9 to 14,
under vacuum at a pressure between 0.75 and 40 mm Hg; and at a
temperature between 50 and 90.degree. C. 27. The process according
to the clause 26, wherein the drying is preferably performed at a
pressure between 0.75 and 20 mm Hg, more preferably between 0.75
and 3 mm Hg, most preferably between 1.5 and 2.25 mm Hg. 28. The
process according to any of the two preceding clauses, wherein the
drying is preferably performed at a temperature between 60 and
80.degree. C., more preferably at 80.degree. C. 29. A process for
preparing arformoterol tartrate form D, as defined in any of the
clauses 1 to 8, from other polymorphic forms of arformoterol
tartrate, comprising the steps of: [0156] a) providing a mixture of
arformoterol tartrate and a solvent selected from an alcohol, water
and mixtures thereof, at temperature between 60 and 70.degree. C.;
[0157] b) cooling the mixture obtained in step (a) to a temperature
between 50 and 55.degree. C.; [0158] c) adding acetonitrile to the
mixture obtained in step (b) until a suspension is obtained; [0159]
d) cooling the suspension obtained in step (c) while stirring to a
temperature between 10 and 30.degree. C. to obtain a solid; and
[0160] e) collecting the crystals obtained in step (d) and drying
the crystals under vacuum at a pressure between 0.75 and 40 mm Hg
and at a temperature between 50 and 90.degree. C. to yield
arformoterol tartrate form D; [0161] wherein when the solvent used
in step in step (a) is a mixture of alcohol and water, the ratio of
alcohol: water is between 1:1 and 1:9. 30. The process according to
clause 29, wherein the alcohol used in step (a) is preferably
selected from methanol, ethanol and isopropanol. 31. The process
according to the preceding clause, wherein the preferred alcohol
used in step (a) is methanol or ethanol. 32. The process according
to any of the clauses 29 to 31, wherein the solvent of step (a) is
a mixture of alcohol/water in a ratio between 1:1 and 1:5. 33. The
process according to the preceding clause, wherein the ratio of the
mixture of alcohol/water is preferably between 1:1 and 1:4. 34. The
process according to clauses 29 to 33, wherein the temperature of
the mixture of step (a) is preferably between 60 and 65.degree. C.
35. The process according to any of the clauses 29 to 34, wherein
the ratio of the solvent used in step (a) and the acetonitrile used
in step (c) is at least 1:1, preferably between 1:1 and 1:5. 36.
The process according to the preceding clause, wherein the ratio
the solvent used in step (a) and the acetonitrile used in step (c)
is preferably between 1:2 and 1:4. 37. The process according to any
of the clauses 29 to 36, wherein the drying carried out in step (e)
is preferably performed at a pressure between 0.75 and 20 mm Hg,
more preferably between 0.75 and 3 mm Hg, most preferably between
1.5 and 2.25 mm Hg. 38. The process according to the any of the
clauses 29 to 37, wherein the drying is preferably performed at a
pressure between 0.75 and 20 mm Hg, more preferably between 0.75
and 3 mm Hg, most preferably between 1.5 and 2.25 mm Hg. 39. The
process according to any of the clauses 29 to 38, wherein the
drying carried out in step (e) is preferably performed at a
temperature between 60 and 80.degree. C., more preferably at
80.degree. C. 40. A process for preparing arformoterol tartrate
form D, as defined in any of the clauses 1 to 8, from arformoterol
base, comprising the steps of: [0162] a) providing a mixture of
arformoterol base with an alcohol or with a combination of
acetonitrile and an alcohol at a temperature between 15 and
60.degree. C.; [0163] b) adding a solution of L-tartaric acid in a
solvent selected from an alcohol, water and mixtures thereof, to
the mixture obtained in step (a); [0164] c) cooling the mixture of
step (b) to a temperature between 30 and 15.degree. C., when
necessary, followed by stirring to obtain a solid; [0165] d)
further cooling the mixture of step (c) to a temperature between 0
and 10.degree. C.; and [0166] e) collecting the crystals obtained
in step (d) and drying the crystals under inlet air pressure and at
a temperature between 30 and 50.degree. C. to yield arformoterol
tartrate form D; 41. The process according to the clause 40,
wherein the mixture provided in step (a) is a mixture of
arformoterol base with an alcohol, selected from methanol, ethanol,
or isopropanol; preferably methanol or ethanol; more preferably
methanol. 42. The process according to the clause 40, wherein the
solution used in step (b) is a solution of L-tartaric acid in an
alcohol, selected from methanol, ethanol, or isopropanol;
preferably methanol or ethanol; more preferably methanol. 43. The
process according to the clause 40, wherein the alcohol used in
steps (a) and (b) is the same. 44. The process according to any of
the clauses 40 to 43, wherein the alcohol of steps (a) and (b) is
selected from methanol, ethanol and isopropanol. 45. The process
according to the preceding clause, wherein the preferred alcohol
used in step (a) and/or step (b) is methanol or ethanol. 46. The
process according to the preceding clause, wherein the most
preferred alcohol used in step (a) and/or step (b) methanol 47. The
process according to any of the clause 40 to 46, wherein the ratio
of the alcohol/acetonitrile used in step (a) is of at least 1:0.1,
preferably between 1:1 and 1:5 48. The process according to the
preceding clause, wherein the ratio of the alcohol/acetonitrile is
preferably between 1:1 and 1:4. 49. The process according to any of
clauses 40 to 48, wherein the mixture of step (a) is preferably at
a temperature between 20 and 60.degree. C. 50. The process
according to any of the clauses 40 to 49, wherein the temperature
of the cooling carried out in step (d) is preferably between 0 and
5.degree. C. 51. The process according to any of the clauses 40 to
50, wherein the steps (a) to (d) are performed under inert
atmosphere, such as under nitrogen or argon atmosphere; preferably,
under nitrogen atmosphere. 52. The process according to the any of
the clauses 40 to 51, wherein the drying carried out in step (e) is
performed at a pressure of 760 mm Hg. 53. The process according to
the any of the clauses 40 to 52, wherein the drying carried out in
step (e) is performed at a pressure between 0.75 and 40 mm Hg,
without the use of inlet air pressure. 54. The process according to
any of the clauses 40 to 53, wherein the temperature of the drying
carried out in step (e) is preferably between 35 and 45.degree. C.,
more preferably at 40.degree. C. 55. The arformoterol tartrate form
D, as defined in any of the clauses 1 to 8, having at least 30%
(w/w) of form D, preferably from 40% to 90% (w/w), more preferably
form 50% to 80% (w/w) relative to the total weight of form D and
polymorph A. 56. The arformoterol tartrate form D of clause 55,
having between 40 and 50% of the known polymorph A. 57. The
arformoterol tartrate form D of any of the two preceding clauses
characterised by a DSC thermogram showing a first endothermic peak
with an onset at approximately 124-125.degree. C. and a maximum at
approximately 130-131.degree. C.; followed by an exothermic peak
with a maximum of approximately 137-138.degree. C., and a second
endothermic peak with a maximum at approximately 191-192.degree. C.
58. The arformoterol tartrate form D of any of the three preceding
clauses, having a differential scanning calorimetry (DSC) and a
thermogravimetric analysis (TGA) thermograms in accordance with
FIG. 3. 59. A process for preparing the arformoterol tartrate form
D of any of the three preceding clauses, from other polymorphic
forms of arformoterol tartrate, comprising the steps of: [0167] a)
providing a mixture of arformoterol tartrate and a solvent selected
from an alcohol, water and mixtures thereof, at temperature between
60 and 70.degree. C.; [0168] b) cooling the mixture obtained in
step (a) to a temperature between 50 and 55
.degree. C.; [0169] c) adding acetonitrile to the mixture obtained
in step (b) until a suspension is obtained; [0170] d) cooling the
suspension obtained in step (c) while stirring to a temperature
between 10 and 30.degree. C. to obtain a solid; and [0171] e)
collecting the crystals obtained in step (d) and drying the
crystals under vacuum at a pressure 0.75 and 40 mm Hg and at a
temperature between 50 and 90.degree. C.; [0172] wherein the ratio
of alcohol: water used in step (a) is over 1:1 and up to 5:1 60.
The process according to clause 59, wherein the alcohol used in
step (a) is preferably selected from methanol and ethanol. 61. The
process according to the preceding clause, wherein the preferred
alcohol used in step (a) is ethanol. 62. The process according to
clauses 59 to 61, wherein the ratio of the mixture of alcohol/water
of step (a) is preferably between 3:1 and 4:1, more preferably 4:1.
63. The process according to any of clauses 59 to 62, wherein the
temperature of the mixture of step (a) is preferably between 60 and
65.degree. C. 64. The process according to any of the clauses 59 to
63, wherein the ratio of the solvent used in step (a) and the
acetonitrile used in step (c) is at least 1:1, preferably between
1:1 and 1:4. 65. The process according to the preceding clause,
wherein the ratio the solvent used in step (a) and the acetonitrile
used in step (c) is preferably between 1:2 and 1:3. 66. The process
according to any of the clauses 59 to 65, wherein the drying
carried out in step (e) is preferably performed at a pressure
between 0.75 and 20 mm Hg, more preferably between 0.75 and 3 mm
Hg, most preferably between 1.5 and 2.25 mm Hg. 67. The process
according to any of the clauses 59 to 66, wherein the drying
carried out in step (e) is preferably performed at a temperature
between 60 and 80.degree. C. 68. The arformoterol tartrate, as
defined in any of the clauses 1 to 8 or 55 to 58, obtained or
obtainable according to the process described in any of the clauses
26 to 54 or 59 to 67. 69. Pharmaceutical composition comprising a
therapeutically effective amount of the arformoterol tartrate
obtained according to any of clauses 26 to 67 and at least one
pharmaceutically acceptable excipient or carrier. 70.
Pharmaceutical composition containing arformoterol tartrate
obtained by mixing form D of arformoterol tartrate according to any
of clauses 1 to 8, and at least one pharmaceutically acceptable
excipient, and its use as a bronchodilator. 71. Pharmaceutical
composition of arformoterol tartrate obtained by mixing form D
according to any of clauses 1-8 and polymorph A in a weight to
weight ratio such that form D is present in an amount of at least
30% (w/w), preferably from 40% to 90% (w/w), more preferably form
50% to 80% (w/w) relative to the total weight of form D and
polymorph A, and at least one pharmaceutically acceptable
excipient, and its use as a bronchodilator. 72. A pharmaceutical
composition comprising a therapeutically effective amount of the
arformoterol tartrate according to any of the clauses 1 to 8, and
55 to 58 and at least one pharmaceutically acceptable excipient or
carrier. 73. The arformoterol tartrate form D according to any of
clauses 1-8, for use as a bronchodilator. 74. The arformoterol
tartrate according to any of clauses 55 to 58, for use as a
bronchodilator. 75. The arformoterol tartrate according to any of
clauses 1 to 8, or 55 to 58, for use as a medicament. 76. The use
of arformoterol tartrate according to any of the clauses 1 to 8, or
55 to 58, as a bronchodilator. 77. A method of effecting
bronchodilation, the method comprising the administration, to a
subject in need of such treatment, of a therapeutically effective
amount of arformoterol tartrate according to any of the clauses 1
to 6, or 53 to 56, or a pharmaceutical composition according to any
of the clauses 67 to 70.
[0173] The present invention is further illustrated by the
following examples. They should in no case be interpreted as a
limitation of the scope of the invention as defined in the
claims.
EXAMPLES
General Methods
[0174] Powder X-Ray Diffraction (PXRD) patterns were acquired on a
D8 Advance Series 2Theta/Theta powder diffraction system using
Cu.sub.K.alpha.1-radiation (1.54060 .ANG.ngstrom) in transmission
geometry. The system was equipped with a V{hacek over (A)}NTEC-1
single photon counting PSD, a Germanium monochromator, a ninety
positions auto changer sample stage, fixed divergence slits and
radial soller. The samples were prepared and placed in standard
sample holders using two foils of polyacetate. One hour scans in a
range from 4.degree. to 40.degree. in 20 were carried out.
Programs used: data collection with DIFFRAC plus XRD Commander
V.2.5.1 and evaluation with EVA V.12.0.
[0175] Differential Scanning calorimetry (DSC) analysis was
recorded in a Mettler Toledo DSC822e calorimeter. Experimental
conditions: 40 .mu.L aluminium crucibles; atmosphere of dry
nitrogen at 50 mL/min flow rate; heating rate of 10.degree. C./min
between 30 and 300.degree. C. Data collection and evaluation was
done with software STARe.
[0176] Thermogravimetric (TGA) analysis was recorded in a Mettler
Toledo SDTA851e thermobalance. Experimental conditions: 40 .mu.L
aluminium crucibles; atmosphere of dry nitrogen at 80 mL/min flow
rate; heating rate of 10.degree. C./min between 30 and 300.degree.
C. Data collection and evaluation was done with software STARe.
Example 1
Synthesis of (R,R)-Formoterol-L-tartrate Form D
[0177] A solution containing 3.9 g (26 mmol) of L-tartaric acid and
36 mL of methanol was added to a solution of 9 g (26 mmol) of
arformoterol base and 144 mL methanol at 23.degree. C. Afterwards,
the resulting mixture was seeded with form D and stirred at
23.degree. C. for 1 hour. It was then further cooled to 0-5.degree.
C. for 1 hour and the product collected by filtration and dried
under inlet air (atmospheric pressure) for 16 hours to provide 11.1
g (86% yield) (99.7% chemical purity, containing 0.14% of the
degradation impurity
(R)-1-(3-amino-4-hydroxyphenyl)-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethy-
l]amino]ethanol) of (R,R)-formoterol L-tartrate form D, as an off
white powder. .sup.1H-NMR (200 MHz, d.sub.6-DMSO) .delta.: 1.03 (d,
3H); 2.50-2.67 (m, 5H); 3.72 (s, 3H); 3.99 (s, 2H); 4.65-4.85 (m,
1H); 6.82-7.15 (m, 5H); 8.02 (s, 1H); 8.28 (s, 1H); 9.60 (s, NH).
No residual solvent was detected (.sup.1H-NMR).
PSD: d.sub.50=2.3 .mu.m.
Example 2.5
Synthesis of (R,R)-Formoterol-L-tartrate Form D
[0178] A solution of 4.2 g (28 mmol) of L-tartaric acid and 36 mL
of methanol was added to a solution of 9.7 g (28 mmol) of
arformoterol base 41 mL methanol and 117 mL acetonitrile at
23.degree. C. Afterwards, the resulting mixture was seeded with
form D and stirred at 23.degree. C. for 1 hour. It was then further
cooled to 0-5.degree. C. for 1 hour and the product collected by
filtration and dried under inlet air (atmospheric pressure) at
40.degree. C. for 16 hours to provide 12.6 g (91% yield) (99.5%
chemical purity) of (R,R)-formoterol L-tartrate form D, as an off
white powder. 1H-NMR (200 MHz, d6-DMSO) .delta.: 1.03 (d, 3H);
2.50-2.67 (m, 5H); 3.72 (s, 3H); 3.99 (s, 2H); 4.65-4.85 (m, 1H);
6.82-7.15 (m, 5H); 8.02 (s, 1H); 8.28 (s, 1H); 9.60 (s, NH). 0.2%
residual (i.e. non-solvated) acetonitrile was detected
(1H-NMR).
Example 3
Synthesis of (R,R)-Formoterol-L-tartrate Form D
[0179] A solution of 4.2 g (28 mmol) of L-tartaric acid and 36 mL
of ethanol was added to a solution of 9.7 g (28 mmol) of
arformoterol base, 41 mL ethanol and 117 mL acetonitrile at
23.degree. C. Then, the resulting mixture was stirred at 23.degree.
C. for 1 hour. It was then further cooled to 0-5.degree. C. for 1
hour and the product collected by filtration. The product was dried
under inlet air (atmospheric pressure) at 40.degree. C. for 16
hours to provide 12.4 g (89% yield) (99% chemical purity) of
(R,R)-formoterol L-tartrate form D, as an off white powder.
.sup.1H-NMR (200 MHz, d6-DMSO) .delta.: 1.03 (d, 3H); 2.50-2.67 (m,
5H); 3.72 (s, 3H); 3.99 (s, 2H); 4.65-4.85 (m, 1H); 6.82-7.15 (m,
5H); 8.02 (s, 1H); 8.28 (s, 1H); 9.60 (s, NH).
Example 4
Synthesis of (R,R)-Formoterol-L-tartrate Form D
[0180] A solution of 4.2 g (28 mmol) of L-tartaric acid and 46 ml
of ethanol was added to a solution of 9.6 g (28 mmol) of
arformoterol base 31 mL ethanol and 117 mL acetonitrile at
60.degree. C. Afterwards, the resulting mixture was cooled at
23.degree. C. and stirred at this temperature for 1 hour. It was
then further cooled to 0-5.degree. C. for 1 hour and the product
collected by filtration and dried under inlet air (atmospheric
pressure) at 40.degree. C. for 16 hours to provide 12.2 g (89%
yield) (99.6% chemical purity) of (R,R)-formoterol L-tartrate form
D, as an off white powder. 1H-NMR (200 MHz, d6-DMSO) .delta.: 1.03
(d, 3H); 2.50-2.67 (m, 5H); 3.72 (s, 3H); 3.99 (s, 2H); 4.65-4.85
(m, 1H); 6.82-7.15 (m, 5H); 8.02 (s, 1H); 8.28 (s, 1H); 9.60 (s,
NH). No residual solvent was detected (1H-NMR).
Example 5
Synthesis of (R,R)-Formoterol-L-tartrate Form D
[0181] A solution of 4.2 g (28 mmol) of L-tartaric acid and 21 mL
of water was added to a solution of 9.7 g (28 mmol) of arformoterol
base, 70 mL methanol and 105 mL acetonitrile at 23.degree. C.
Afterwards, the resulting mixture was seeded with form D and
stirred at this temperature for 1 hour. It was then further cooled
to 0-5.degree. C. for 1 hour and the product collected by
filtration and dried under inlet air (atmospheric pressure) at
40.degree. C. for 16 hours to provide 11.5 g (83% yield) (99.9%
chemical purity) of (R,R)-formoterol L-tartrate form D, as an off
white powder. 1H-NMR (200 MHz, d6-DMSO) .delta.: 1.03 (d, 3H);
2.50-2.67 (m, 5H); 3.72 (s, 3H); 3.99 (s, 2H); 4.65-4.85 (m, 1H);
6.82-7.15 (m, 5H); 8.02 (s, 1H); 8.28 (s, 1H); 9.60 (s, NH). 0.2%
residual (i.e. non-solvated) acetonitrile was detected
(1H-NMR).
Example 6
Synthesis of (R,R)-Formoterol-L-tartrate Form D
[0182] A suspension of 9 g (18 mmol) of arformoterol-L-tartrate
form B and 270 mL of methanol was heated at 60.degree. C. until
solution. Afterwards, to the resulting mixture was added 360 mL of
acetonitrile until a suspension was obtained. The suspension was
cooled at 23.degree. C. and stirred at this temperature for 1 hour.
It was then further cooled to 0-5.degree. C. for 1 hour and the
product collected by filtration and dried inlet air (atmospheric
pressure) at 40.degree. C. for 16 hours to provide 8.1 g (90%
yield) (99.8% chemical purity) of (R,R)-formoterol L-tartrate form
D, as an off white powder. .sup.1H-NMR (200 MHz, d6-DMSO) .delta.:
1.03 (d, 3H); 2.50-2.67 (m, 5H); 3.72 (s, 3H); 3.99 (s, 2H);
4.65-4.85 (m, 1H); 6.82-7.15 (m, 5H); 8.02 (s, 1H); 8.28 (s, 1H);
9.60 (s, NH).
Example 7.5
Synthesis of (R,R)-Formoterol-L-tartrate Form D
[0183] A suspension of 1.073 g (2.16 mmol) of (R,R)-arformoterol
tartrate Form B in 30 mL of methanol was heated to the reflux
temperature of the solvent for 15 minutes until a clear
yellow-orange solution was obtained. Afterwards, it was cooled to
about 60-50.degree. C. and followed by addition of 10 mL aliquots
of acetonitrile (total of 40 mL) at the same temperature until a
suspension was obtained. The suspension was further cooled to
10-40.degree. C. and stirred at this temperature for 10 minutes.
The product was collected by filtration, washed with acetonitrile
and dried under vacuum (2 mbar, equivalent to 1.5 mm Hg) at
80.degree. C. for 15 hours to provide 773 mg (73% yield) of
(R,R)-formoterol L-tartrate form D, which contained no solvent
detected by 1H-NMR or TGA analysis.
Example 8
Synthesis of Acetonitrile Solvate of
(R,R)-Formoterol-L-tartrate
[0184] A suspension of 348.8 mg (0.70 mmol) of (R,R)-arformoterol
tartrate Form B in 15 mL of methanol was heated to the reflux
temperature of the solvent for 15 minutes or until a clear yellow
solution was obtained. Afterwards, it was cooled to about
60-50.degree. C. and followed by addition of 5 mL aliquots of
acetonitrile (total of 45 mL) at the same temperature until a
suspension was obtained. The suspension was further cooled to
10-40.degree. C. and stirred at this temperature for 10 minutes.
The product was collected by filtration, washed with acetonitrile
and dried under vacuum (2 mbar, equivalent to 1.5 mm Hg) at
40.degree. C. for 12 hours to provide 262.4 mg (75% yield) of
acetonitrile solvate of (R,R)-Formoterol-L-tartrate, which
contained acetonitrile in a range between 2 and 4% (w/w), as
determined by 1H-NMR or TGA analysis.
Example 9
Synthesis of (R,R)-Formoterol-L-tartrate Form D
[0185] Acetonitrile solvate of (R,R)-Formoterol-L-tartrate prepared
according to example 8, was dried under vacuum (2 mbar, equivalent
to 1.5 mm Hg) at 80.degree. C. for 16 hours to obtain
(R,R)-Formoterol-L-tartrate form D, which contained no solvent
detected by .sup.1H-NMR or TGA analysis.
Example 10
Synthesis of Acetonitrile Solvate of
(R,R)-Formoterol-L-tartrate
[0186] A suspension of 135 mg (0.27 mmol) of (R,R)-arformoterol
tartrate Form A and 7.5 mL of methanol was heated to the reflux
temperature of the solvent for 10 min. Then, the solution obtained
was allowed to cool to about 50-60.degree. C., followed by addition
of 19 mL of acetonitrile at the same temperature. Afterwards, the
solution was cooled to room temperature and stirred for 1 hour. The
product was collected by filtration, washed with acetonitrile and
dried under vacuum (2-3 mbar, equivalent to 1.5-2.25 mm Hg) at
25.degree. C. for 1 hour to provide acetonitrile solvate of
(R,R)-Formoterol-L-tartrate, which contained about 2.5% (w/w) of
acetonitrile, as determined by 1H-NMR analysis.
Example 11
Synthesis of (R,R)-Formoterol-L-tartrate Form D
[0187] Acetonitrile solvate of (R,R)-Formoterol-L-tartrate prepared
according to example 10 was dried under vacuum (2-3 mbar,
equivalent to 1.5-2.25 mm Hg) at 80.degree. C. for 1 hour to obtain
(R,R)-Formoterol-L-tartrate form D, which contained no solvent
detected by TGA analysis.
Example 13
Synthesis of Acetonitrile Solvate of
(R,R)-Formoterol-L-tartrate
[0188] A suspension of 407.3 mg (0.82 mmol) of (R,R)-arformoterol
tartrate Form B and 15 mL of methanol was heated to the reflux
temperature of the solvent for 15 min. Then, the solution obtained
was allowed to cool to about 50-60.degree. C., followed by addition
of 45 mL of acetonitrile at the same temperature. Afterwards, the
solution was cooled to room temperature and stirred for 30 minutes.
The product was collected by filtration, washed with acetonitrile
and dried under vacuum (2-3 mbar, equivalent to 1.5-2.25 mm Hg) at
60.degree. C. for 2 hours to provide 345.5 mg (85% yield) of
acetonitrile solvate of (R,R)-Formoterol-L-tartrate, which
contained about 1.6% (w/w) of acetonitrile, as determined by TGA
analysis.
Example 14
Synthesis of Acetonitrile Solvate of
(R,R)-Formoterol-L-tartrate
[0189] A suspension of 1.007 g (2 mmol) of (R,R)-arformoterol
tartrate Form A and 65 mL of methanol was heated to the reflux
temperature of the solvent for 30 min. Then, the solution obtained
was cooled to 50.degree. C. in 30 min, followed by addition of 90
mL of acetonitrile at the same temperature for 10 minutes.
Afterwards, the solution was cooled to 30.degree. C. in 30 minutes
and stirred at room temperature for 2 hours. The product was
collected by filtration, washed with acetonitrile and dried under
vacuum (2-3 mbar, equivalent to 1.5-2.25 mm Hg) at 40.degree. C.
for 17 hours to provide acetonitrile solvate of
(R,R)-Formoterol-L-tartrate, which contained about 2.7% (w/w) of
acetonitrile, as determined by TGA analysis.
Example 15
Synthesis of (R,R)-Formoterol-L-tartrate Form D
[0190] Acetonitrile solvate of (R,R)-Formoterol-L-tartrate prepared
according to example 14 was dried under vacuum (2-3 mbar,
equivalent to 1.5-2.25 mm Hg) at 60.degree. C. for 2 hours to
obtain (R,R)-Formoterol-L-tartrate form D (55% yield) (99.9%
chemical purity), which contained no solvent detected by TGA
analysis.
Example 16
Synthesis of (R,R)-Formoterol-L-tartrate Form D
[0191] 216.7 mg (0.44 mmol) of (R,R)-arformoterol tartrate Form A
were suspended in 1 mL of a mixture of methanol/water (ratio 1:1)
and heated to a temperature between 60 and 70.degree. C. for 10
min. Then, the solution obtained was allowed to cool to about
50-60.degree. C., followed by addition of 4 mL of acetonitrile at
the same temperature. Afterwards, the solution was cooled to room
temperature and stirred for 1 hour. The product was collected by
filtration, washed with acetonitrile and dried under vacuum (2-3
mbar, equivalent to 1.5-2.25 mm Hg) at 80.degree. C. for 2 hours to
provide 150.5 mg (69% yield) (99.92% chemical purity) of
(R,R)-formoterol L-tartrate form D, which contained no solvent
detected by 1H-NMR or TGA analysis.
Example 17
Synthesis of (R,R)-Formoterol-L-tartrate Form D
[0192] 262 mg (0.53 mmol) of (R,R)-arformoterol tartrate Form A
were suspended in 1 mL of a mixture of ethanol/water (ratio 1:1)
and heated to a temperature between 60 and 70.degree. C. for 10
min. Then, the solution obtained was allowed to cool to about
50-60.degree. C., followed by addition of 3 mL of acetonitrile at
the same temperature. Afterwards, the solution was cooled to room
temperature and stirred for 1 hour. The product was collected by
filtration, washed with acetonitrile and dried under vacuum (2-3
mbar, equivalent to 1.5-2.25 mm Hg) at 80.degree. C. for 2 hours to
provide 193.3 mg (74% yield) (99.94% chemical purity) of
(R,R)-formoterol L-tartrate form D, which contained no solvent
detected by 1H-NMR or TGA analysis.
Example 18
Synthesis of (R,R)-Formoterol-L-tartrate Form D
[0193] 323.2 mg (0.65 mmol) of (R,R)-arformoterol tartrate Form A
were suspended in 1 mL of a mixture of ethanol/water (ratio 1:4)
and heated to a temperature between 60 and 70.degree. C. for 10
min. Then, the solution obtained was allowed to cool to about
50-60.degree. C., followed by addition of 3 mL of acetonitrile at
the same temperature. Afterwards, the solution was cooled to room
temperature and stirred for 1 hour. The product was collected by
filtration, washed with acetonitrile and dried under vacuum (2-3
mbar, equivalent to 1.5-2.25 mm Hg) at 80.degree. C. for 2 hours to
provide 233 mg (72% yield) (99.94% chemical purity) of
(R,R)-formoterol L-tartrate form D, which contained no solvent
detected by 1H-NMR or TGA analysis.
Example 19
Synthesis of (R,R)-Formoterol-L-tartrate Form D
[0194] 215.5 mg (0.44 mmol) of (R,R)-arformoterol tartrate Form A
were suspended in 1 mL of a mixture of isopropanol/water (ratio
1:1) and heated to a temperature between 60 and 70.degree. C. for
10 min. Then, the solution obtained was allowed to cool to about
50-60.degree. C., followed by addition of 3 mL of acetonitrile at
the same temperature. Afterwards, the solution was cooled to room
temperature and stirred for 1 hour. The product was collected by
filtration, washed with acetonitrile and dried under vacuum (2-3
mbar, equivalent to 1.5-2.25 mm Hg) at 80.degree. C. for 2 hours to
provide 130 mg (60% yield) of (R,R)-formoterol L-tartrate form D,
which contained no solvent detected by 1H-NMR or TGA analysis.
Example 20
Synthesis of Form D of (R,R)-Formoterol L-tartrate, Using
Arformoterol Base as Starting Material
[0195] A solution of 4.2 g (28 mmol) of L-tartaric acid and 21 mL
of water was added to a solution of 9.7 g (28 mmol) of arformoterol
base, 70 mL ethanol and 105 mL acetonitrile at 60.degree. C.
Afterwards, the resulting mixture was seeded with form D cooled at
23.degree. C. and stirred at this temperature for 1 hour. It was
then further cooled to 0-5.degree. C. for 1 hour and the product
collected by filtration and dried under inlet air (atmospheric
pressure) at 40.degree. C. for 16 hours to provide 12.2 g (88%
yield) (99.9% chemical purity, containing 0.05% of the degradation
impurity
(R)-1-(3-amino-4-hydroxyphenyl)-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethy-
l]amino]ethanol) of form D of (R,R)-formoterol L-tartrate, as an
off white powder, containing less than 1% of Polymorph A. 1H-NMR
(200 MHz, d6-DMSO) .delta.: 1.03 (d, 3H); 2.50-2.67 (m, 5H); 3.72
(s, 3H); 3.99 (s, 2H); 4.65-4.85 (m, 1H); 6.82-7.15 (m, 5H); 8.02
(s, 1H); 8.28 (s, 1H); 9.60 (s, NH).
Example 21
Synthesis of a Mixture of Form D and Polymorph a of
(R,R)-Formoterol L-tartrate, Using Arformoterol Tartrate Polymorph
a as Starting Material
[0196] 318.4 mg (0.64 mmol) of (R,R)-arformoterol tartrate Form A
were suspended in 1 mL of a mixture of methanol/water (ratio 4:1)
and heated to a temperature between 60 and 70.degree. C. for 10
min. Then, the solution obtained was allowed to cool to about
50-60.degree. C., followed by addition of 3 mL of acetonitrile at
the same temperature. Afterwards, the solution was cooled to room
temperature and stirred for 1 hour. The product was collected by
filtration, washed with acetonitrile and dried under vacuum (2-3
mbar, equivalent to 1.5-2.25 mm Hg) at 80.degree. C. for 2 hours to
provide 278.8 mg (88% yield) (99.65% chemical purity) of a mixture
of form D and polymorph A of (R,R)-formoterol L-tartrate, which
contained no solvent detected by 1H-NMR or TGA analysis.
Characterisation Examples
Solubility of (R,R)-Formoterol-L-tartrate Form D
[0197] Different amounts of (R,R)-Formoterol-L-tartrate form A, B,
C or D, and a mixture of forms A and D, were weighed separately and
0.5 mL of milliQ water were added. The suspensions obtained were
stirred at 25.degree. C. for 1 hour in a Crystal 16 equipment,
which included a turbidity detection system that allowed
determining if a solute had dissolved completely. The results
obtained showed a concentration range, wherein the minor value
indicated the highest concentration at which the solute dissolved
completely, and the major value indicated the lowest concentration
at which solute did not completely dissolve. The results are
summarized in Table 1. Depending on the exact methods by which the
various arformoterol tartrate polymorphs were prepared, a range of
particle sizes and degrees of crystallinity were observed. The
particle size (d.sub.50 value; i.e. the median diameter) was
generally found to range from 1 to 100 .mu.m. As a result of the
variation in particle size and degree of crystallinity, however, a
range of different solubilities were observed for each given
polymorph, as reported below.
[0198] According to The United States Pharmacopeia, 24.sup.th ed.,
it can be defined that form A and form B are sparingly soluble in
water, while, significantly, new form D is soluble in water.
TABLE-US-00005 TABLE 1 Solubility assays of different polymorphic
forms of (R,R)-Formoterol-L-tartrate Solubility as described in
(R,R)-Formoterol-L- Solubility range U.S. Pat. No. tartrate
polymorphic form (mg/mL) 6,268,533 (mg/mL) form A 14-17 15.4 form B
24-32 26.7 form C 12-18 form D 38-83 Mixture form A/form D
14-17
Stability of (R,R)-Formoterol-L-tartrate Form D and Acetonitrile
Solvate of (R,R)-Formoterol-L-tartrate
[0199] Stability assays of (R,R)-Formoterol-L-tartrate form D and
an acetonitrile solvate of (R,R)-Formoterol-L-tartrate obtained as
described above were performed at different conditions of
temperature (T=5-7.degree. C. and room temperature) after 7, 18, 30
and 90 days. The samples were placed in a vial under atmospheric
pressure, under vacuum and under inert atmosphere. The results are
shown in Table 2 and prove that form D is stable.
TABLE-US-00006 TABLE 2 Stability assays of
(R,R)-Formoterol-L-tartrate form D and acetonitrile solvate of
(R,R)-Formoterol-L-tartrate Stability test conditions Atmospheric
Atmospheric Inert Vacuum pressure, pressure atmosphere at room Temp
= 5-7.degree. C. at room Temp at room Temp Temp after 7 after 30
after 90 after 18 after 30 after 90 after 30 after 90 After 30
after 90 Example days days days days days days days days days days
15 form D form D form D form D form D form D form D form D form D
form D 13 acetonitrile acetonitrile acetonitrile solvate solvate
solvate
* * * * *